Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation- induced hepatic injury

Wen Hong Kan, Jun Te Hsu, Martin G. Schwacha, Mashkoor A. Choudhry, Raghavan Pillai Raju, Kirby I. Bland, Irshad H. Chaudry

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Although trauma-hemorrhage produces tissue hypoxia, systemic inflammatory response and organ dysfunction, the mechanisms responsible for these alterations are not clear. Using a potent selective inducible nitric oxide (NO) synthase inhibitor, N-[3-(aminomethyl) benzyl]acetamidine (1400W), and a nonselective NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), we investigated whether inducible NO synthase plays any role in producing hepatic injury, inflammation, and changes of protein expression following trauma-hemorrhage. To investigate this, male Sprague-Dawley rats were subjected to midline laparotomy and hemorrhagic shock (mean blood pressure 35-40 mmHg for ∼90 min) followed by fluid resuscitation. Animals were treated with either vehicle (DMSO) or 1400W (10 mg/kg body wt ip), or L-NAME (30 mg/kg iv), 30 min before resuscitation and killed 2 h after resuscitation. Trauma-hemorrhage/ resuscitation induced a marked hypotension and increase in markers of hepatic injury (i.e., plasma α-glutathione S-transferase, tissue myeloperoxidase activity, and nitrotyrosine formation). Hepatic expression of iNOS, hypoxia-inducible factor-1α, ICAM-1, IL-6, TNF-α, and neutrophil chemoattractant (cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2) protein levels were also markedly increased following trauma-hemorrhage/ resuscitation. Administration of the iNOS inhibitor 1400W significantly attenuated hypotension and expression of these mediators of hepatic injury induced by trauma-hemorrhage/resuscitation. However, administration of L-NAME could not attenuate hepatic dysfunction and tissue injury mediated by trauma-hemorrhage, although it improved mean blood pressure as did 1400W. These results indicate that increased expression of iNOS following trauma-hemorrhage plays an important role in the induction of hepatic damage under such conditions.

Original languageEnglish (US)
Pages (from-to)1076-1082
Number of pages7
JournalJournal of Applied Physiology
Volume105
Issue number4
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

Fingerprint

Resuscitation
Hemorrhage
Liver
Wounds and Injuries
NG-Nitroarginine Methyl Ester
Chemotactic Factors
Nitric Oxide Synthase Type II
Hypotension
Neutrophils
Chemokine CXCL2
Blood Pressure
Hypoxia-Inducible Factor 1
Hemorrhagic Shock
Intercellular Adhesion Molecule-1
Dimethyl Sulfoxide
Glutathione Transferase
Nitric Oxide Synthase
Laparotomy
Peroxidase
Sprague Dawley Rats

Keywords

  • Chemokine
  • Cytokine
  • Hypoxia-inducible factor-1α
  • Myeloperoxidase activity

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation- induced hepatic injury. / Kan, Wen Hong; Hsu, Jun Te; Schwacha, Martin G.; Choudhry, Mashkoor A.; Raju, Raghavan Pillai; Bland, Kirby I.; Chaudry, Irshad H.

In: Journal of Applied Physiology, Vol. 105, No. 4, 01.10.2008, p. 1076-1082.

Research output: Contribution to journalArticle

Kan, Wen Hong ; Hsu, Jun Te ; Schwacha, Martin G. ; Choudhry, Mashkoor A. ; Raju, Raghavan Pillai ; Bland, Kirby I. ; Chaudry, Irshad H. / Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation- induced hepatic injury. In: Journal of Applied Physiology. 2008 ; Vol. 105, No. 4. pp. 1076-1082.
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AU - Raju, Raghavan Pillai

AU - Bland, Kirby I.

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